CN112999219B - Common amorphous substance containing andrographolide, and its preparation method and pharmaceutical composition - Google Patents
Common amorphous substance containing andrographolide, and its preparation method and pharmaceutical composition Download PDFInfo
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Abstract
The invention relates to the technical field of medicines, and particularly relates to an andrographolide-containing co-amorphous substance, a preparation method thereof and a pharmaceutical composition. The co-amorphous substance is formed by combining andrographolide with a component A, a component B, a component C or a component D; the component A is oxymatrine, the component B is oxymatrine and cinnamic acid, the component C is oxymatrine and p-hydroxycinnamic acid, and the component D is oxymatrine and ferulic acid. The pharmaceutical composition comprises the common amorphous substance containing andrographolide. The andrographolide-containing co-amorphous substance can remarkably improve the solubility and dissolution rate of andrographolide.
Description
Technical Field
The invention relates to the technical field of medicines, and in particular relates to a common amorphous substance containing andrographolide, a preparation method thereof and a pharmaceutical composition.
Background
Andrographolide (AP) is a diterpene lactone bioactive substance extracted from herba Andrographitis, CAS number is 5508-58-7, and its chemical formula is C20H30O5It is widely used in traditional medicine in China, India and southeast Asia. Has wide pharmacological actions of resisting tumor, bacteria, inflammation, virus, growth, cardiovascular system diseases and the like. In particular, it has special therapeutic effect on bacterial and viral upper respiratory tract infections, and is called "natural antibiotic". Andrographolide and its various preparations have been listed as essential in emergency department by Ministry of health and State administration of traditional Chinese medicine.
The andrographolide is a fat-soluble medicine, has poor water solubility and low bioavailability when being taken orally, and is related to metabolic transformation of andrographolide sulfate and derivatives thereof after being taken orally, so that the inhibition or reduction of the sulfated transformation of andrographolide is beneficial to improving the oral bioavailability of andrographolide.
At present, a plurality of methods for improving the solubility of andrographolide exist, and the andrographolide cyclodextrin inclusion compound prepared by spray drying andrographolide and beta-CD in a molar ratio of 1:1 in patent CN102343096A greatly increases the solubility, bioavailability and stability of andrographolide, but has the defects of enhanced toxicity and increased preparation cost. Patent CN108354905A discloses the preparation of andrographolide solid dispersion, and patent CN104983688A provides a feasible method for preparing andrographolide nano-crystals, and water is used as a solvent, so that the method is safe, cheap and easy to industrialize. Patent CN106038578 discloses a nano micelle of andrographolide and glycyrrhizin, which can improve the dissolution rate and bioavailability of andrographolide, and simultaneously, stability is significantly improved compared with a nano crystal preparation because glycyrrhizin has natural pharmacological activity and can be administered with andrographolide in a synergistic manner.
Oxymematrine (OX) is an alkaloid extracted from radix Sophorae Flavescentis, and has CAS number of 16837-52-8 and chemical formula of C15H24N2O2. Have traditionally been used against hepatitis b virus, anti-inflammatory and anti-allergic reactions. Has been proved to have better effects in the aspects of antibiosis, metabolism regulation and fibrosis resistance.
Cinnamic Acid (CA) is a natural organic acid present in plants, CAS number 140-10-3, and has chemical formula C9H8O2. It has low toxicity and wide biological activity, and is often used as a starting compound for developing new and highly effective drugs. Cinnamic acid is reported to have antibacterial, antiviral and antifungal effects. Therefore, cinnamic acid is an important and promising compound and has great development potential.
p-Hydroxycinnamic acid (pHCA) is an intermediate metabolite present in various fruits, plants and vegetables, a natural organic acid synthesized from tyrosine. CAS number 7400-08-0, and chemical formula C9H8O3. Pharmacologically, it has many biological effects such as antioxidation, antiallergic, antibacterial and immunoregulation.
Ferulic Acid (FA) is one of cinnamic acid derivatives, CAS number 1135-24-6, and its chemical formula C10H10O4. Ferulic acid (sodium ferulate) has effects of resisting platelet aggregation, inhibiting release of platelet 5-hydroxytryptamine, inhibiting generation of platelet thromboxane a2(txa2), enhancing prostaglandin activity, relieving pain, and relieving vasospasm.
Co-amorphous is a unidirectional amorphous system composed of two or more small molecule components. The components can be connected by non-covalent bonds such as hydrogen bonds, pi-pi stacking and the like or have no interaction force. It is customary to assign a co-amorphous form to a solid dispersion, but it still exhibits differences in physicochemical properties from solid dispersions. Compared with the crystal drug, the co-amorphous form not only can improve the solubility and the dissolution rate, but also has certain influence on the melting point and the compressibility of the drug. In addition, the co-amorphous drug can be used for directionally selecting auxiliary materials with pharmacological effects, and has the potential of synergistic drug delivery to a certain extent. Therefore, the co-amorphous form has become more and more an international research hotspot for drugs, and has important significance for prolonging the life of the original drugs and developing new drugs.
Disclosure of Invention
The invention aims to solve the problem of low solubility and dissolution rate of andrographolide which is an active ingredient of a traditional Chinese medicine in the prior art, and provides an andrographolide-containing co-amorphous substance, a preparation method thereof and a pharmaceutical composition.
In order to achieve the above objects, the present invention provides, in one aspect, a co-amorphous containing andrographolide, the co-amorphous being formed by andrographolide in combination with component a, component B, component C or component D;
the component A is oxymatrine, the component B is oxymatrine and cinnamic acid, the component C is oxymatrine and p-hydroxycinnamic acid, and the component D is oxymatrine and ferulic acid.
Preferably, the co-amorphous substance uses Cu-K alpha radiation, and has no sharp crystal diffraction peak in an X-ray powder diffraction pattern.
Preferably, when the co-amorphous substance is formed by combining andrographolide with component A;
the infrared absorption spectrum of the co-amorphous substance is 3407cm by KBr tablet measurement-1、2933cm-1、1754cm-1、1613cm-1、1442cm-1、1348cm-1、1289cm-1、1250cm-1、1204cm-1、1186cm-1、1163cm-1、1130cm-1、1083cm-1、1040cm-1、989cm-1、956cm-1、886cm-1、864cm-1、831cm-1、776cm-1、670cm-1、633cm-1、570cm-1、490cm-1、457cm-1、431cm-1Has an absorption peak;
preferably, the glass transition temperature of the co-amorphous is 75.1 ℃;
preferably, the molar ratio of andrographolide to oxymatrine is 1: 1.
Preferably, when the co-amorphous substance is formed by combining andrographolide with component B;
the infrared absorption spectrum measured by KBr pellet is 3381cm-1、2940cm-1、1754cm-1、1674cm-1、1614cm-1、1449cm-1、1379cm-1、1251cm-1、1188cm-1、1080cm-1、1038cm-1、904cm-1、877cm-1、776cm-1、717cm-1、688cm-1、635cm-1、585cm-1、535cm-1、488cm-1、428cm-1Has an absorption peak;
preferably, the glass transition temperature of the co-amorphous is 76.5 ℃;
preferably, the molar ratio of andrographolide, oxymatrine and cinnamic acid is 1:1: 1.
Preferably, when the co-amorphous substance is formed by combining andrographolide with component C;
the infrared absorption spectrum measured by KBr pellet is 3377cm-1、2940cm-1、1754cm-1、1606cm-1、1514cm-1、1445cm-1、1376cm-1、1281cm-1、1250cm-1、1168cm-1、1080cm-1、1035cm-1、984cm-1、863cm-1、634cm-1、523cm-1Has an absorption peak;
preferably, the glass transition temperature of the co-amorphous is 60.6 ℃;
preferably, the molar ratio of andrographolide, oxymatrine and p-hydroxycinnamic acid is 1:1: 1.
Preferably, when the co-amorphous substance is formed by combining andrographolide with component D;
the infrared absorption spectrum measured by KBr pellet is 3377cm-1、2938cm-1、1754cm-1、1675cm-1、1608cm-1、1514cm-1、1464cm-1、1378cm-1、1279cm-1、1185cm-1、1125cm-1、1080cm-1、1034cm-1、983cm-1、850cm-1、634cm-1、571cm-1Has an absorption peak;
preferably, the glass transition temperature of the co-amorphous is 71.6 ℃;
preferably, the molar ratio of andrographolide, oxymatrine and ferulic acid is 1:1: 1.
In a second aspect of the present invention, there is provided a method for preparing the above andrographolide-containing co-amorphous form, the method comprising the steps of: dissolving andrographolide and component A, component B, component C or component D in organic solvent at a certain ratio, filtering, and performing rotary evaporation under reduced pressure and drying.
Preferably, the temperature of the reduced-pressure rotary evaporation is 36-60 ℃;
preferably, the organic solvent is selected from at least one of methanol, ethanol and acetonitrile.
In a third aspect, the invention provides a pharmaceutical composition comprising the above-mentioned andrographolide-containing co-amorphous material.
Preferably, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.
The invention has the beneficial effects that:
1. the amorphous substance containing andrographolide is different from andrographolide, oxymatrine, cinnamic acid, p-hydroxy cinnamic acid, ferulic acid and the powder X-ray diffraction pattern, DSC spectrogram and infrared spectrum of the physical mixture of the raw materials in the amorphous substance preparation, so the amorphous substance is a new solid state completely different from each monomer and the physical mixture thereof.
2. After the andrographolide and other components are prepared into an amorphous substance, the solubility and the dissolution rate of the andrographolide in the amorphous substance are obviously improved compared with those of a single andrographolide crystal, the andrographolide is expected to become a new raw material solid form of a compound preparation containing andrographolide, and the andrographolide compound preparation has a good development prospect.
Drawings
FIGS. 1a to 1f are the results of powder X-ray diffraction tests of andrographolide crystals, oxymatrine crystals, cinnamic acid crystals, p-hydroxycinnamic acid crystals, ferulic acid crystals and methionine crystals in comparative example 1;
FIGS. 2a to 2e are powder X-ray diffraction test results of the physical mixture of andrographolide crystals and oxymatrine crystals in test example 1, the physical mixture of andrographolide crystals, oxymatrine crystals and cinnamic acid crystals, the physical mixture of andrographolide crystals, oxymatrine crystals and p-hydroxycinnamic acid crystals, the physical mixture of andrographolide crystals, oxymatrine crystals and ferulic acid crystals, and the physical mixture of andrographolide crystals and methionine crystals in comparative example 1;
FIGS. 3a-3e are powder X-ray diffraction test results of four co-amorphous forms of test example 1 and a rotary evaporation product of andrographolide-methionine of comparative example 1;
FIGS. 4a to 4e are the results of differential scanning calorimetry of the andrographolide crystals, oxymatrine crystals, cinnamic acid crystals, p-hydroxycinnamic acid crystals and ferulic acid crystals of test example 2;
FIGS. 5a to 5d are the results of differential scanning calorimetry test of the physical mixture of andrographolide crystals and oxymatrine crystals, the physical mixture of andrographolide crystals, oxymatrine crystals and cinnamic acid crystals, the physical mixture of andrographolide crystals, oxymatrine crystals and p-hydroxycinnamic acid crystals, and the physical mixture of andrographolide crystals, oxymatrine crystals and ferulic acid crystals in test example 2;
FIGS. 6a-6d are differential scanning calorimetry test results for the four co-amorphous forms of test example 2;
FIGS. 7a to 7e are the results of IR spectroscopy on andrographolide crystals, oxymatrine crystals, cinnamic acid crystals, p-hydroxycinnamic acid crystals and ferulic acid crystals in test example 3;
FIGS. 8a to 8d are the results of IR spectroscopy of the physical mixture of andrographolide crystals and oxymatrine crystals, the physical mixture of andrographolide crystals, oxymatrine crystals and cinnamic acid crystals, the physical mixture of andrographolide crystals, oxymatrine crystals and p-hydroxycinnamic acid crystals, and the physical mixture of andrographolide crystals, oxymatrine crystals and ferulic acid crystals in test example 3;
FIGS. 9a-9d are differential scanning calorimetry test results for the four co-amorphous forms of test example 3;
fig. 10a to 10d are characteristic dissolution curves of andrographolide in buffer at pH4.1 for the four co-amorphous forms of test example 5.
Detailed Description
The following describes in detail embodiments of the present invention with reference to the drawings. It should be understood that the detailed description and specific examples, while indicating the present invention, are given by way of illustration and explanation only, not limitation.
The endpoints of the ranges and any values disclosed herein are not limited to the precise range or value, and such ranges or values should be understood to encompass values close to those ranges or values. For ranges of values, between the endpoints of each of the ranges and the individual points, and between the individual points may be combined with each other to give one or more new ranges of values, and these ranges of values should be considered as specifically disclosed herein.
The invention provides a common amorphous substance containing andrographolide, which is formed by combining andrographolide with a component A, a component B, a component C or a component D;
the component A is oxymatrine, the component B is oxymatrine and cinnamic acid, the component C is oxymatrine and p-hydroxycinnamic acid, and the component D is oxymatrine and ferulic acid.
In the invention, 4 kinds of co-amorphous substances are provided, namely an andrographolide-oxymatrine co-amorphous substance, an andrographolide-oxymatrine-cinnamic acid co-amorphous substance, an andrographolide-oxymatrine-p-hydroxycinnamic acid co-amorphous substance and an andrographolide-oxymatrine-ferulic acid co-amorphous substance.
In the invention, the co-amorphous substance uses Cu-Ka radiation, and has no sharp crystal diffraction peak in an X-ray powder diffraction pattern.
In the invention, when the co-amorphous substance is formed by combining andrographolide and the component A, namely the andrographolide-oxymatrine co-amorphous substance, the infrared absorption spectrum of the co-amorphous substance measured by KBr tablet is 3407cm-1、2933cm-1、1754cm-1、1613cm-1、1442cm-1、1348cm-1、1289cm-1、1250cm-1、1204cm-1、1186cm-1、1163cm-1、1130cm-1、1083cm-1、1040cm-1、989cm-1、956cm-1、886cm-1、864cm-1、831cm-1、776cm-1、670cm-1、633cm-1、570cm-1、490cm-1、457cm-1、431cm-1Has an absorption peak.
In a preferred embodiment, when the co-amorphous form is formed by combining andrographolide with component a, namely, an andrographolide-oxymatrine co-amorphous form, the glass transition temperature of the co-amorphous form is 75.1 ℃.
In a preferred embodiment, when the co-amorphous form is formed by combining andrographolide with component a, namely, an andrographolide-oxymatrine co-amorphous form, the molar ratio of andrographolide to oxymatrine is 1: 1.
In the invention, the amorphous substance is formed by andrographolide and andrographolideWhen the component B is formed by combination, namely the andrographolide-oxymatrine-cinnamic acid co-amorphous substance, an infrared absorption spectrum obtained by KBr tablet measurement is 3381cm-1、2940cm-1、1754cm-1、1674cm-1、1614cm-1、1449cm-1、1379cm-1、1251cm-1、1188cm-1、1080cm-1、1038cm-1、904cm-1、877cm-1、776cm-1、717cm-1、688cm-1、635cm-1、585cm-1、535cm-1、488cm-1、428cm-1Has an absorption peak.
In a preferred embodiment, when the co-amorphous form is formed by combining andrographolide with component B, namely, the andrographolide-oxymatrine-cinnamic acid co-amorphous form, the glass transition temperature of the co-amorphous form is 76.5 ℃.
In a preferred embodiment, when the co-amorphous substance is formed by combining andrographolide with component B, namely, the andrographolide-oxymatrine-cinnamic acid co-amorphous substance, the molar ratio of andrographolide to oxymatrine to cinnamic acid is 1:1: 1.
In the invention, when the amorphous substance is formed by combining andrographolide and component C, namely the andrographolide-oxymatrine-p-hydroxycinnamic acid amorphous substance, an infrared absorption spectrum obtained by KBr tablet measurement is 3377cm-1、2940cm-1、1754cm-1、1606cm-1、1514cm-1、1445cm-1、1376cm-1、1281cm-1、1250cm-1、1168cm-1、1080cm-1、1035cm-1、984cm-1、863cm-1、634cm-1、523cm-1Has an absorption peak;
in a preferred embodiment, when the co-amorphous form is formed by combining andrographolide with component C, namely, the andrographolide-oxymatrine-p-hydroxycinnamic acid co-amorphous form, the glass transition temperature of the co-amorphous form is 60.6 ℃.
In a preferred embodiment, when the co-amorphous substance is formed by combining andrographolide with component C, namely, the andrographolide-oxymatrine-p-hydroxycinnamic acid co-amorphous substance, the molar ratio of andrographolide, oxymatrine and p-hydroxycinnamic acid is 1:1: 1.
In the invention, when the amorphous substance is formed by combining andrographolide and the component D, namely the andrographolide-oxymatrine-ferulic acid amorphous substance, the infrared absorption spectrum obtained by KBr tablet measurement is 3377cm-1、2938cm-1、1754cm-1、1675cm-1、1608cm-1、1514cm-1、1464cm-1、1378cm-1、1279cm-1、1185cm-1、1125cm-1、1080cm-1、1034cm-1、983cm-1、850cm-1、634cm-1、571cm-1Has an absorption peak.
In a preferred embodiment, when the co-amorphous form is formed by combining andrographolide with component D, i.e. an andrographolide-oxymatrine-ferulic acid co-amorphous form, the glass transition temperature of the co-amorphous form is 71.6 ℃.
In a preferred embodiment, when the co-amorphous form is formed by combining andrographolide with component D, i.e. an andrographolide-oxymatrine-ferulic acid co-amorphous form, the molar ratio of andrographolide, oxymatrine and ferulic acid is 1:1: 1.
In a second aspect of the present invention, there is provided a method for preparing the above andrographolide-containing co-amorphous form, the method comprising the steps of: dissolving andrographolide and component A, component B, component C or component D in organic solvent at a certain ratio, filtering, and performing rotary evaporation under reduced pressure and drying.
In a preferred embodiment, the preparation method comprises the following specific steps:
(1) dissolving andrographolide and component A, component B, component C or component D in organic solvent according to a ratio to obtain a clear solution;
(2) carrying out reduced pressure rotary evaporation on the solution obtained in the step (1) to obtain a solid product;
(3) and (3) drying the solid product obtained in the step (2) in vacuum to remove residual solvent to obtain the andrographolide-containing co-amorphous substance.
In a preferred embodiment, the temperature of the reduced pressure rotary evaporation is 36-60 ℃; further preferably, the temperature of the reduced pressure rotary evaporation is 45-55 ℃.
In a preferred embodiment, the organic solvent is selected from at least one of methanol, ethanol and acetonitrile.
In a third aspect, the invention provides a pharmaceutical composition comprising the above-mentioned andrographolide-containing co-amorphous form.
Preferably, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.
The pharmaceutical composition is prepared by taking the common amorphous substance containing andrographolide as an active ingredient and preparing a medicament with a pharmaceutically acceptable carrier.
The pharmaceutical composition may be in any form suitable for administration: such as: tablets (including sugar-coated tablets, film tablets, enteric-coated tablets, sustained-release tablets and the like), capsules (including hard capsules, soft capsules and sustained-release capsules), oral liquids, granules, pills, powders, drops, buccal agents, granules, pastes, pellets, suspensions, powders, solutions, injections, suppositories, sprays and the like.
For the pharmaceutical compositions of the present invention, formulations for oral administration may contain conventional excipients such as binding agents, fillers, tabletting agents, lubricants, colorants, flavors, and wetting agents.
The pharmaceutical composition of the present invention can be prepared into solid oral compositions by mixing, filling, tabletting and the like, which are methods commonly used in the art.
The present invention will be described in detail below by way of examples, but the scope of the present invention is not limited thereto.
Example 1
Preparing an andrographolide-oxymatrine amorphous substance: adding 0.2g andrographolide and 0.15g oxymatrine (molar ratio is 1:1) into 50mL methanol, ultrasonically stirring at room temperature to dissolve to obtain clear solution, filtering, performing rotary evaporation on the filtrate at 52 ℃ under reduced pressure, and vacuum drying at 25 ℃ for 24h to obtain white powder 0.28 g.
Preparing an andrographolide-oxymatrine-cinnamic acid co-amorphous substance: adding 0.2g of andrographolide, 0.15g of oxymatrine and 0.084g of cinnamic acid (molar ratio is 1:1:1) into 50mL of methanol, ultrasonically stirring at room temperature to dissolve the andrographolide to obtain a clear solution, filtering, performing rotary evaporation on the filtrate at 52 ℃ under reduced pressure, and performing vacuum drying at 25 ℃ for 24 hours to obtain 0.31g of white powder.
Preparing an andrographolide-oxymatrine-p-hydroxycinnamic acid co-amorphous substance: adding 0.2g of andrographolide, 0.15g of oxymatrine and 0.094g of p-hydroxycinnamic acid (molar ratio is 1:1:1) into 50mL of methanol, ultrasonically stirring at room temperature to dissolve the andrographolide to obtain a clear solution, filtering the clear solution, performing rotary evaporation on the filtrate at 52 ℃ under reduced pressure to remove the solvent, and performing vacuum drying at 25 ℃ for 24 hours to obtain 0.30g of white powder.
Preparing andrographolide-oxymatrine-ferulic acid amorphous substance: adding 0.2g andrographolide, 0.15g oxymatrine and 0.11g ferulic acid (molar ratio is 1:1:1) into 50mL methanol, stirring at room temperature with ultrasound to dissolve to obtain clear solution, filtering, performing rotary evaporation on the filtrate at 52 deg.C under reduced pressure, and vacuum drying at 25 deg.C for 24h to obtain white powder 0.32 g.
Example 2
Preparing an andrographolide-oxymatrine amorphous substance: adding 0.2g andrographolide and 0.15g oxymatrine (molar ratio is 1:1) into 50mL ethanol, ultrasonically stirring at room temperature to dissolve to obtain clear solution, filtering, performing rotary evaporation on the filtrate at 42 ℃ under reduced pressure, and vacuum drying at 25 ℃ for 24h to obtain white powder 0.29 g.
Preparing an andrographolide-oxymatrine-cinnamic acid co-amorphous substance: adding 0.2g of andrographolide, 0.15g of oxymatrine and 0.084g of cinnamic acid (molar ratio is 1:1:1) into 50mL of ethanol, ultrasonically stirring at room temperature to dissolve the andrographolide to obtain a clear solution, filtering, performing rotary evaporation on the filtrate at 42 ℃ under reduced pressure, and performing vacuum drying at 25 ℃ for 24 hours to obtain 0.30g of white powder.
Preparing an andrographolide-oxymatrine-p-hydroxycinnamic acid co-amorphous substance: adding 0.2g of andrographolide, 0.15g of oxymatrine and 0.094g of p-hydroxycinnamic acid (molar ratio is 1:1:1) into 50mL of ethanol, ultrasonically stirring at room temperature to dissolve the andrographolide to obtain a clear solution, filtering the clear solution, performing rotary evaporation on the filtrate at 42 ℃ under reduced pressure to remove the solvent, and performing vacuum drying at 25 ℃ for 24 hours to obtain 0.29g of white powder.
Preparing andrographolide-oxymatrine-ferulic acid amorphous substance: adding 0.2g andrographolide, 0.15g oxymatrine and 0.11g ferulic acid (molar ratio is 1:1:1) into 50mL ethanol, stirring at room temperature with ultrasound to dissolve to obtain clear solution, filtering, performing rotary evaporation on the filtrate at 42 deg.C under reduced pressure, and vacuum drying at 25 deg.C for 24h to obtain white powder 0.33 g.
Example 3
Preparing an andrographolide-oxymatrine amorphous substance: adding 0.2g andrographolide and 0.15g oxymatrine (molar ratio is 1:1) into 50mL acetonitrile, ultrasonically stirring at room temperature to dissolve to obtain clear solution, filtering, performing rotary evaporation on the filtrate at 45 ℃ under reduced pressure, and performing vacuum drying at 25 ℃ for 24h to obtain 0.29g white powder.
Preparing an andrographolide-oxymatrine-cinnamic acid co-amorphous substance: adding 0.2g of andrographolide, 0.15g of oxymatrine and 0.084g of cinnamic acid (molar ratio is 1:1:1) into 50mL of acetonitrile, ultrasonically stirring at room temperature to dissolve the andrographolide to obtain a clear solution, filtering, performing rotary evaporation on the filtrate at 45 ℃ under reduced pressure, and performing vacuum drying at 25 ℃ for 24 hours to obtain 0.31g of white powder.
Preparing an andrographolide-oxymatrine-p-hydroxycinnamic acid co-amorphous substance: adding 0.2g of andrographolide, 0.15g of oxymatrine and 0.094g of p-hydroxycinnamic acid (molar ratio is 1:1:1) into 50mL of acetonitrile, ultrasonically stirring at room temperature to dissolve the andrographolide to obtain a clear solution, filtering, performing rotary evaporation on the filtrate at 45 ℃ under reduced pressure to remove the solvent, and performing vacuum drying at 25 ℃ for 24 hours to obtain 0.32g of white powder.
Preparing andrographolide-oxymatrine-ferulic acid amorphous substance: adding 0.2g andrographolide, 0.15g oxymatrine and 0.11g ferulic acid (molar ratio is 1:1:1) into 50mL acetonitrile, ultrasonically stirring at room temperature for dissolving to obtain clear solution, filtering, performing rotary evaporation on the filtrate at 45 ℃ under reduced pressure, and performing vacuum drying at 25 ℃ for 24h to obtain 0.33g white powder.
Example 4
Preparing an andrographolide-oxymatrine amorphous substance: adding 0.2g andrographolide and 0.15g oxymatrine (molar ratio is 1:1) into 50mL methanol-ethanol (50:50, v/v) mixed solvent, stirring and dissolving with ultrasound at room temperature to obtain clear solution, filtering, performing rotary evaporation on the filtrate at 46 ℃ under reduced pressure, and drying at 25 ℃ under vacuum for 24h to obtain 0.31g white powder.
Preparing an andrographolide-oxymatrine-cinnamic acid co-amorphous substance: adding 0.2g of andrographolide, 0.15g of oxymatrine and 0.084g of cinnamic acid (molar ratio is 1:1:1) into 50mL of methanol-ethanol (50:50, v/v) mixed solvent, ultrasonically stirring and dissolving at room temperature to obtain clear solution, filtering, carrying out reduced pressure rotary evaporation on the solvent at 46 ℃, and carrying out vacuum drying at 25 ℃ for 24h to obtain 0.32g of white powder.
Preparing an andrographolide-oxymatrine-p-hydroxycinnamic acid co-amorphous substance: adding 0.2g of andrographolide, 0.15g of oxymatrine and 0.094g of p-hydroxycinnamic acid (molar ratio is 1:1:1) into 50mL of methanol-ethanol (50:50, v/v) mixed solvent, ultrasonically stirring at room temperature to dissolve to obtain clear solution, filtering, carrying out rotary evaporation on the solvent at 46 ℃ under reduced pressure, and carrying out vacuum drying at 25 ℃ for 24 hours to obtain 0.33g of white powder.
Preparing andrographolide-oxymatrine-ferulic acid amorphous substance: adding 0.2g andrographolide, 0.15g oxymatrine and 0.11g ferulic acid (molar ratio is 1:1:1) into 50mL methanol-ethanol (50:50, v/v) mixed solvent, ultrasonically stirring at room temperature to dissolve to obtain clear solution, filtering, performing rotary evaporation of the solvent under reduced pressure at 46 ℃, and vacuum drying at 25 ℃ for 24h to obtain 0.34g white powder.
Comparative example 1
Andrographolide and methionine attempted to prepare a co-amorphous: adding 0.2g andrographolide and 0.08g methionine (molar ratio of 1:1) into 50mL methanol, dissolving at room temperature under ultrasonic stirring to obtain clear solution, filtering, rotary evaporating solvent under reduced pressure at 52 deg.C, and vacuum drying at 25 deg.C for 24 hr to obtain white powder 0.22 g.
Test example 1
The 4 kinds of co-amorphous, amorphous and physical mixtures of the preparative raw materials obtained in example 1, the rotary evaporated product obtained in comparative example 1, the preparative raw materials of the rotary evaporated product and the physical mixtures of the preparative raw materials were examined using powder X-ray diffraction, wherein the instrument models were: d8Advance/3 KWX-ray diffractometer (Bruker AXS, Germany), the instrument parameters included: target: Cu-Kalpha radiation; wavelength:
pipe pressure: 40 KV; pipe flow: 40 mA; step length: 0.02 degree; scanning speed: 10 °/min.
The test results of andrographolide crystal are shown in fig. 1a, the test results of oxymatrine crystal are shown in fig. 1b, the test results of cinnamic acid crystal are shown in fig. 1c, the test results of hydroxycinnamic acid crystal are shown in fig. 1d, the test results of ferulic acid crystal are shown in fig. 1e, and the test results of methionine crystal are shown in fig. 1 f; the test results of the physical mixture of andrographolide crystals and oxymatrine crystals are shown in fig. 2a, the test results of the physical mixture of andrographolide crystals, oxymatrine crystals and cinnamic acid crystals are shown in fig. 2b, the test results of the physical mixture of andrographolide crystals, oxymatrine crystals and p-hydroxycinnamic acid crystals are shown in fig. 2c, the test results of the physical mixture of andrographolide crystals, oxymatrine crystals and ferulic acid crystals are shown in fig. 2d, and the test results of the physical mixture of andrographolide crystals and methionine crystals are shown in fig. 2 e; the test results of the andrographolide-oxymatrine co-amorphous form prepared in example 1 are shown in fig. 3a, the test results of the andrographolide-oxymatrine-cinnamic acid co-amorphous form prepared in example 1 are shown in fig. 3b, the test results of the andrographolide-oxymatrine-p-hydroxycinnamic acid co-amorphous form prepared in example 1 are shown in fig. 3c, the test results of the andrographolide-oxymatrine-ferulic acid co-amorphous form prepared in example 1 are shown in fig. 3d, and the test results of the andrographolide-methionine co-rotary evaporation product prepared in comparative example 1 are shown in fig. 3 e.
As can be seen from the figure, the spectrum of the co-amorphous obtained in example 1 has no sharp diffraction peak, and is completely different from the spectrum of the raw material for preparing the amorphous and the spectrum of the physical mixture of the raw material for preparing the amorphous. The spectrum of the rotary evaporated product obtained in comparative example 1 has sharp diffraction peaks, which are substantially the same as the spectrum of the physical mixture of the starting materials for the preparation of the rotary evaporated product, and andrographolide and methionine cannot be prepared in this way to obtain a co-amorphous form.
Test example 2
The 4 kinds of co-amorphous materials, amorphous material preparation raw materials and physical mixture of the preparation raw materials prepared in example 1 were detected by Differential Scanning Calorimetry (DSC), wherein the instrument models are: TA-DSC2500 differential scanning calorimeter (Waters, USA), instrument parameters including: the range is as follows: 25-300 ℃; temperature rise rate: 10 ℃/min.
And (3) testing results: the test results of andrographolide crystal are shown in fig. 4a, oxymatrine crystal is shown in fig. 4b, cinnamic acid crystal is shown in fig. 4c, hydroxycinnamic acid crystal is shown in fig. 4d, and ferulic acid crystal is shown in fig. 4 e; the test results of the physical mixture of andrographolide crystals and oxymatrine crystals are shown in fig. 5a, the test results of the physical mixture of andrographolide crystals, oxymatrine crystals and cinnamic acid crystals are shown in fig. 5b, the test results of the physical mixture of andrographolide crystals, oxymatrine crystals and p-hydroxycinnamic acid crystals are shown in fig. 5c, and the test results of the physical mixture of andrographolide crystals, oxymatrine crystals and ferulic acid crystals are shown in fig. 5 d; the test results of the andrographolide-oxymatrine co-amorphous form are shown in fig. 6a, the test results of the andrographolide-oxymatrine-cinnamic acid co-amorphous form are shown in fig. 6b, the test results of the andrographolide-oxymatrine-p-hydroxycinnamic acid co-amorphous form are shown in fig. 6c, and the test results of the andrographolide-oxymatrine-ferulic acid co-amorphous form are shown in fig. 6 d.
As can be seen from the figure, the endothermic transition of andrographolide is 236.4 ℃, the endothermic transition of oxymatrine is 162.8 ℃, the endothermic transition of cinnamic acid is 134.2 ℃, the endothermic transition of p-hydroxycinnamic acid is 222.8 ℃, the endothermic transition of ferulic acid is 161.3 ℃, the glass transition temperature of an andrographolide-oxymatrine co-amorphous substance is 75.1 ℃, the glass transition temperature of an andrographolide-oxymatrine-cinnamic acid co-amorphous substance is 76.5 ℃, the glass transition temperature of an andrographolide-oxymatrine-p-hydroxycinnamic acid co-amorphous substance is 60.6 ℃, and the glass transition temperature of an andrographolide-oxymatrine-ferulic acid co-amorphous substance is 71.6 ℃.
Test example 3
The 4 kinds of co-amorphous and amorphous preparation raw materials and physical mixtures of the preparation raw materials prepared in example 1 were examined by infrared spectroscopy (FT-IR), wherein the instrument models are: nicolet Impact 410 Infrared Spectroscopy (Thermo Fisher Scientific, USA), KBr pellet.
And (3) testing results: the test results of andrographolide crystal are shown in fig. 7a, oxymatrine crystal is shown in fig. 7b, cinnamic acid crystal is shown in fig. 7c, hydroxycinnamic acid crystal is shown in fig. 7d, and ferulic acid crystal is shown in fig. 7 e; the test results of the physical mixture of andrographolide crystals and oxymatrine crystals are shown in fig. 8a, the test results of the physical mixture of andrographolide crystals, oxymatrine crystals and cinnamic acid crystals are shown in fig. 8b, the test results of the physical mixture of andrographolide crystals, oxymatrine crystals and p-hydroxycinnamic acid crystals are shown in fig. 8c, and the test results of the physical mixture of andrographolide crystals, oxymatrine crystals and ferulic acid crystals are shown in fig. 8 d; the test results of the andrographolide-oxymatrine co-amorphous form are shown in fig. 9a, the test results of the andrographolide-oxymatrine-cinnamic acid co-amorphous form are shown in fig. 9b, the test results of the andrographolide-oxymatrine-p-hydroxycinnamic acid co-amorphous form are shown in fig. 9c, and the test results of the andrographolide-oxymatrine-ferulic acid co-amorphous form are shown in fig. 9 d.
As shown in the figure, the common amorphous form of andrographolide-oxymatrineThe wave number of the infrared spectrum of the substance is as follows: 3407cm-1、2933cm-1、1754cm-1、1613cm-1、1442cm-1、1348cm-1、1289cm-1、1250cm-1、1204cm-1、1186cm-1、1163cm-1、1130cm-1、1083cm-1、1040cm-1、989cm-1、956cm-1、886cm-1、864cm-1、831cm-1、776cm-1、670cm-1、633cm-1、570cm-1、490cm-1、457cm-1、431cm-1(ii) a The wave number of the amorphous substance of andrographolide-oxymatrine-cinnamic acid is as follows: 3381cm-1、2940cm-1、1754cm-1、1674cm-1、1614cm-1、1449cm-1、1379cm-1、1251cm-1、1188cm-1、1080cm-1、1038cm-1、904cm-1、877cm-1、776cm-1、717cm-1、688cm-1、635cm-1、585cm-1、535cm-1、488cm-1、428cm-1(ii) a The wave number of the amorphous substance of andrographolide-oxymatrine-p-hydroxycinnamic acid in the infrared spectrum is as follows: 3377cm-1、2940cm-1、1754cm-1、1606cm-1、1514cm-1、1445cm-1、1376cm-1、1281cm-1、1250cm-1、1168cm-1、1080cm-1、1035cm-1、984cm-1、863cm-1、634cm-1、523cm-1(ii) a The wave number of the andrographolide-oxymatrine-ferulic acid amorphous substance infrared spectrum is as follows: 3377cm-1、2938cm-1、1754cm-1、1675cm-1、1608cm-1、1514cm-1、1464cm-1、1378cm-1、1279cm-1、1185cm-1、1125cm-1、1080cm-1、1034cm-1、983cm-1、850cm-1、634cm-1、571cm-1。
Test example 4
The 4 kinds of co-amorphous substances prepared in example 1 were measured for equilibrium solubility and compared with the mixture of andrographolide bulk drug and the raw material for preparation, as follows:
the solubility determination method is as follows:
the solubility of andrographolide in water and various pH buffers was determined. 10mL of different media (water, 0.1 mol. L) were measured separately-1Hydrochloric acid solution, acetic acid buffer solution with pH4.1, phosphoric acid buffer solution with pH6.8, phosphoric acid buffer solution with pH 7.6) is placed in a 15mL EP tube, the EP tube is sealed and placed in a water bath constant temperature oscillator with 25 ℃ after excessive substances to be detected are added, shaking is carried out for 24h to achieve balance, standing is carried out for 30min, supernate is removed and filtered by a 0.22 mu m microporous filter membrane, continuous filtration and sample injection are carried out, the solubility is measured by High Performance Liquid Chromatography (HPLC), and each group of samples are parallelly measured for 3 times. The high performance liquid chromatography conditions were as follows:
the instrument comprises the following steps: shimadzu LC-20A high performance liquid chromatograph
A chromatographic column: fortis C18 chromatographic column (250X 4.6mm, 5 μm)
Column temperature: 30 deg.C
Mobile phase: methanol-Water (55:45) (V/V)
Flow rate: 1.0mL/min
Detection wavelength: 225nm
The linear equation of andrographolide is A-26135.4C +6845.4 (R)20.99996) linear range of 5 pg/mL-1～500μg·mL-1And the relative standard deviation of the parallel measurement is less than 2 percent, which shows that the method has good repeatability and high accuracy.
The detection results are as follows:
1. the equilibrium solubility (μ g/mL) of andrographolide bulk drug, the andrographolide-oxymatrine co-amorphous form prepared in example 1, and a physical mixture of andrographolide and oxymatrine in buffered salt solutions of different pH values and ultrapure water are shown in table 1.
TABLE 1
2. The equilibrium solubility (μ g/mL) of andrographolide bulk drug, the andrographolide oxymatrine-cinnamic acid co-amorphous form prepared in example 1, and a physical mixture of andrographolide, oxymatrine, and cinnamic acid in buffered salt solutions of different pH values and ultrapure water is shown in table 2.
TABLE 2
3. The equilibrium solubility (μ g/mL) of andrographolide bulk drug, the andrographolide oxymatrine-p-hydroxycinnamic acid co-amorphous form prepared in example 1, and a physical mixture of andrographolide, oxymatrine, and p-hydroxycinnamic acid in buffered salt solutions of different pH values and ultrapure water is shown in table 3.
TABLE 3
4. The equilibrium solubilities (μ g/mL) of andrographolide bulk drug, the andrographolide-oxymatrine-ferulic acid co-amorphous form prepared in example 1, and a physical mixture of andrographolide, oxymatrine, and ferulic acid in buffered salt solutions of different pH values and ultrapure water are shown in table 4.
TABLE 4
From the above test results, it can be seen that, when andrographolide and other components are made into an amorphous form, the solubility of andrographolide in the amorphous form is significantly improved compared with that of a single andrographolide crystal.
Test example 5
The characteristic dissolution rate of the co-amorphous form and the andrographolide crystals obtained in example 1 was measured.
The specific method comprises the following steps:
the method comprises the steps of enabling andrographolide crystals, andrographolide-oxymatrine amorphous substances, andrographolide-oxymatrine-cinnamic acid amorphous substances, andrographolide-oxymatrine-p-hydroxycinnamic acid amorphous substances and andrographolide-oxymatrine-ferulic acid amorphous substances to pass through a 100-mesh sieve (150 mu m), precisely weighing 200mg of solid powder, and respectively compressing at room temperature for 10s under the pressure of 115.2MPa to form a glass disc. A surface area of 0.5024cm was obtained2Dense and structured tablets, coated with beeswax on three sides to obtain a flat surface, with only one circular surface in contact with the dissolution medium. Dissolution test method according to the first method (basket method) of 0931 of the general rule of 2020 edition of Chinese pharmacopoeia, the determination medium is acetate buffer solution with pH4.1, the volume of the medium is 900mL, the rotating speed is 50rpm, and the dissolution medium temperature is 37 ℃. After the start of the test, samples were taken at 5, 10, 15, 20, 30, 45, 60, 90 and 120min, 3mL each, and 3mL of dissolution medium was replenished. The solution was removed and filtered through a 0.22 μm microporous membrane, and the filtrate was subjected to HPLC analysis in parallel for 6 times. The chromatographic conditions were consistent with those under the solubility assay. Characteristic dissolution Rate through the amount of dissolution (mg. cm)-2) -the slope of the time (min) regression curve.
And (3) testing results:
1. the characteristic dissolution curve of andrographolide in the buffer solution with pH of 4.1 of the original andrographolide crystal and andrographolide-oxymatrine co-amorphous substance is shown in figure 10a, and the characteristic dissolution rate of andrographolide in the andrographolide-oxymatrine co-amorphous substance within 0-30min is about 6.3 times of the characteristic dissolution rate of andrographolide in the original andrographolide crystal; the characteristic dissolution rate of andrographolide in 30-120min andrographolide-oxymatrine amorphous substance is about 2.5 times of that of andrographolide in original andrographolide crystal.
2. The characteristic dissolution curve of andrographolide in the buffer solution with pH of 4.1 of the original andrographolide crystal and the andrographolide-oxymatrine-cinnamic acid co-amorphous substance is shown in figure 10b, and the characteristic dissolution rate of andrographolide in the andrographolide-oxymatrine-cinnamic acid co-amorphous substance is about 11.5 times of the characteristic dissolution rate of andrographolide in the original andrographolide crystal.
3. The characteristic dissolution curve of andrographolide in buffer solution with pH of 4.1 of the original andrographolide crystal and andrographolide-oxymatrine-p-hydroxycinnamic acid co-amorphous form is shown in figure 10c, and the characteristic dissolution rate of andrographolide in andrographolide-oxymatrine-p-hydroxycinnamic acid co-amorphous form is about 11.5 times of the characteristic dissolution rate of andrographolide in original andrographolide crystal.
4. The characteristic dissolution curve of andrographolide in buffer solution with pH of 4.1 of the original andrographolide crystal and andrographolide-oxymatrine-ferulic acid co-amorphous substance is shown in figure 10d, and the characteristic dissolution rate of andrographolide in andrographolide-oxymatrine-ferulic acid co-amorphous substance is about 10.9 times of the characteristic dissolution rate of andrographolide in original andrographolide crystal.
From the test results, after the andrographolide and other components are prepared into an amorphous substance, the dissolution rate of the andrographolide in the amorphous substance is obviously improved compared with that of a single andrographolide crystal.
The preferred embodiments of the present invention have been described above in detail, but the present invention is not limited thereto. Within the scope of the technical idea of the invention, many simple modifications can be made to the technical solution of the invention, including combinations of various technical features in any other suitable way, and these simple modifications and combinations should also be regarded as the disclosure of the invention, and all fall within the scope of the invention.
Claims (12)
1. A co-amorphous substance containing andrographolide, which is characterized in that the co-amorphous substance is formed by combining andrographolide with a component A, a component B, a component C or a component D;
the component A is oxymatrine, the component B is oxymatrine and cinnamic acid, the component C is oxymatrine and p-hydroxycinnamic acid, and the component D is oxymatrine and ferulic acid;
when the co-amorphous substance is formed by combining andrographolide and the component A, the molar ratio of andrographolide to oxymatrine is 1: 1;
when the co-amorphous substance is formed by combining andrographolide and the component B, the molar ratio of andrographolide, oxymatrine and cinnamic acid is 1:1: 1;
when the co-amorphous substance is formed by combining andrographolide and component C, the molar ratio of andrographolide, oxymatrine and p-hydroxycinnamic acid is 1:1: 1;
when the co-amorphous substance is formed by combining andrographolide and the component D, the molar ratio of andrographolide, oxymatrine and ferulic acid is 1:1: 1;
the method for preparing the co-amorphous material comprises the following steps: dissolving andrographolide and component A, component B, component C or component D in organic solvent according to a ratio, filtering, and performing reduced pressure rotary evaporation and drying on the filtrate;
the temperature of the reduced pressure rotary evaporation is 36-60 ℃;
the organic solvent is selected from at least one of methanol, ethanol and acetonitrile.
2. The andrographolide-containing co-amorphous form according to claim 1, wherein the co-amorphous form is free of sharp crystalline diffraction peaks in an X-ray powder diffraction pattern by using Cu-Ka radiation.
3. The andrographolide-containing co-amorphous substance according to claim 1 or 2, wherein when the co-amorphous substance is formed by combining andrographolide with component A;
the infrared absorption spectrum of the co-amorphous substance is 3407cm by KBr tablet measurement-1、2933cm-1、1754cm-1、1613cm-1、1442cm-1、1348cm-1、1289cm-1、1250cm-1、1204cm-1、1186cm-1、1163cm-1、1130cm-1、1083cm-1、1040cm-1、989cm-1、956cm-1、886cm-1、864cm-1、831cm-1、776cm-1、670cm-1、633cm-1、570cm-1、490cm-1、457cm-1、431cm-1Has an absorption peak.
4. The andrographolide-containing co-amorphous form according to claim 3, wherein the glass transition temperature of the co-amorphous form is 75.1 ℃.
5. The andrographolide-containing co-amorphous form according to claim 1 or 2, wherein when the co-amorphous form is formed by combining andrographolide with component B;
the infrared absorption spectrum measured by KBr pellet is 3381cm-1、2940cm-1、1754cm-1、1674cm-1、1614cm-1、1449cm-1、1379cm-1、1251cm-1、1188cm-1、1080cm-1、1038cm-1、904cm-1、877cm-1、776cm-1、717cm-1、688cm-1、635cm-1、585cm-1、535cm-1、488cm-1、428cm-1Has an absorption peak.
6. The andrographolide-containing co-amorphous form according to claim 5, wherein the glass transition temperature of the co-amorphous form is 76.5 ℃.
7. The andrographolide-containing co-amorphous form according to claim 1 or 2, wherein when the co-amorphous form is formed by combining andrographolide with component C;
the infrared absorption spectrum measured by KBr pellet is 3377cm-1、2940cm-1、1754cm-1、1606cm-1、1514cm-1、1445cm-1、1376cm-1、1281cm-1、1250cm-1、1168cm-1、1080cm-1、1035cm-1、984cm-1、863cm-1、634cm-1、523cm-1Has an absorption peak.
8. The andrographolide-containing co-amorphous form according to claim 7, wherein the glass transition temperature of the co-amorphous form is 60.6 ℃.
9. The andrographolide-containing co-amorphous form according to claim 1 or 2, wherein when the co-amorphous form is formed by combining andrographolide with component D;
the infrared absorption spectrum measured by KBr pellet is 3377cm-1、2938cm-1、1754cm-1、1675cm-1、1608cm-1、1514cm-1、1464cm-1、1378cm-1、1279cm-1、1185cm-1、1125cm-1、1080cm-1、1034cm-1、983cm-1、850cm-1、634cm-1、571cm-1Has an absorption peak.
10. The andrographolide-containing co-amorphous form according to claim 9, wherein the glass transition temperature of the co-amorphous form is 71.6 ℃.
11. A pharmaceutical composition comprising the andrographolide-containing co-amorphous form of any one of claims 1-10.
12. The pharmaceutical composition of claim 11, further comprising a pharmaceutically acceptable carrier.
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